Repellent substances generally cause insects to be driven away from, or to reject, otherwise insect-acceptable food sources or habitats. Most known repellents are only mildly toxic. A few of the known repellents, in fact, are not active poisons at all but rather prevent damage to plants/animals or articles of manufacture by making insect food sources or living conditions unattractive or offensive. Most current commercial insect repellents contain the synthetic chemical N,N-diethyl-m-toluamide (DEET) as their primary active ingredient. For instance, repellents sold under the major commercial brand names such as Off!®, Deep Woods Off!®, and Cutter® are all DEET based products and comprise 85% of insect repellent sales (Consumer Reports Buying Guide, 1994 Special Year-End Issue). Further, Consumer Reports tests indicated that products with the highest concentration of DEET lasted the longest against mosquitoes.
Despite being an effective repellent, however, this compound has certain drawbacks. Specifically, it possesses an unpleasant odor and imparts a greasy feel to the skin. Although it has recently been re-registered for use in the US by the EPA, concerns have been raised as to its safety, particularly when applied to children [Briassoulis, G.; Narlioglou, M.; Hatzis, T. (2001) Human & Experimental Toxicology 20(1), 8-14]. Studies have demonstrated that high concentrations of DEET may give rise to allergic or toxic reactions in some individuals. Other disadvantages associated with DEET include that it (1) is a synthetic chemical having a limited spectrum of activity; (2) is a powerful plasticizer and will dissolve or mar many plastics and painted surfaces; and (3) plasticizes the inert ingredients typically used in topical formulations in order to lengthen the time of effectiveness. This leads to DEET formulations with low user acceptability.
As a result of the above limitations, DEET-free products with repellent activity are finding favor with consumers, and demand for compositions containing natural products (versus synthetic chemicals such as DEET) is increasing. These DEET-free repellent compounds require a combination of excellent repellency, high residual activity and relatively little or no toxicity to humans (or pets) and the environment. In response to these consumer demands, there is an on-going need to develop new repellent compounds, which can be obtained from, or synthesized from, natural plant materials and which are pleasant to use.
Many plant species produce essential oils (aromatic oils) that are used as natural sources of insect repellent and fragrant chemicals [Hay, R. K. M., Svoboda, K. P., Botany, in “Volatile Oil Crops: their biology, chemistry and production”; Hay, R. K. M., Waterman, P. G. (eds.); Longman Group UK Limited (1993)]. Citronella oil, known for its general repellence towards insects, is obtained from the graminaceous plants Cymbopogon winterianus and C. nardus. Examples of plants used as sources of fragrant chemicals include Melissa officinalis (Melissa), Perilla frutescens (Perilla), Posostemon cablin (Patchouli) and various Lavandula spp. (Lavender). All of these examples of plants yielding oil of value to the fragrance industry are members of the Labiatae (Lamiaceae) family. Plants of the genus Nepeta (catmints) are also members of this family, and produce an essential oil, which is a minor item of commerce. This oil is very rich in a class of monoterpenoid compounds known as iridoids [Inouye, H. Iridoids. Methods in Plant Biochemistry 7:99-143 (1991)], more specifically the methylcyclopentanoid nepetalactones [Clark, L. J. et al. The Plant Journal, 11:1387-1393 (1997)] and derivatives.
Iridoid monoterpenoids have long been known to be effective repellents to a variety of insect species [Eisner, T. Science 146:1318-1320 (1964); Eisner, T. Science 148:966-968 (1965); Peterson, C. and J. Coats, Pesticide Outlook 12:154-158 (2001); and Peterson, C. et al. Abstracts of Papers American Chemical Society, (2001) 222 (1-2): AGRO73]. U.S. Pat. No. 4,663,346 discloses insect repellants with compositions containing bicyclic iridoid lactones (e.g., iridomyrmecin). Further, U.S. Pat. No. 4,869,896 discloses use of these bicyclic iridoid lactone compositions in potentiated insect repellent mixtures with DEET.
Formal studies concerning the repellency of dihydronepetalactones, a class of iridoid monoterpenoids derived from nepetalactones (shown in FIG. 1), have been much less conclusive and have failed to teach or imply that these compounds exert a repellent effect on the common insect pests of human society. For example, a study of the composition of the secretion from anal glands of the ant Iridomyrmex nitidus showed that isodihydronepetalactone was present in appreciable amounts, together with isoiridomyrmecin [Cavill, G. W. K., and D. V. Clark. J. Insect Physiol. 13:131-135 (1967)]. Although isoiridomyrmecin was known at the time to possess good ‘knockdown’ insecticidal activity, no evidence was provided in support of a similar activity for isodihydronepetalactone, and no investigation of this compound's repellent effect (as distinct from insecticidal activity) was made.
In a later publication by Cavill, G. W. K., et al. [Tetrahedron 38:1931-1938 (1982)], the presence of dihydronepetalactones in the defensive secretion of an ant was again reported, but the authors concluded that the compound iridodial, rather than a dihydronepetalactone, was the basic repellent constituent.

Most recently, Jefson, M., et al. [J. Chemical Ecology 9:159-180 (1983)] described the repellent effect of dihydronepetalactone. Initial repellency caused by the undiluted compound was measured with respect to the ant species Monomorium destructor during feeding. After 25 seconds of exposure to the pure dihydronepetalactone, approximately 50-60% of the ants ceased to feed. However, further analyses of the repellency over a longer time course were not presented, nor were analyses with anything other than the pure undiluted compound. Repellency observed over such short periods of time (seconds) with concentrated chemicals is insufficient to allow prediction of efficacy in practical applications such as in topical insect repellents.
There is consequently a continuing need for a biologically based compound having improved insect repellent properties (with respect to DEET) and which is substantially non-toxic or only mildly toxic to humans. Preferred repellents will have activity against a wide variety of insects, including biting insects, wood-boring insects, noxious insects, household pests, and the like. Applicants have found that dihydronepetalactones, and compositions thereof, perform well as a new class of effective insect repellent compounds without the disadvantageous properties characteristic of prior-art compositions.